We, the present inventors, already synthetized and provided N-methyl-D,L-threo-3-(3,4-dihydroxyphenyl)serine and N-methyl-L-threo-3-(3,4-dihydroxyphenyl)serine, and N-methyl-L-threo-3-(3,4-dihydroxyphenyl)serine may also be termed as L-threo-adrenalinecarboxylic acid and is a compound which is able to penetrate into the brain of mammalian animals when administered intravenously and to increase the levels of the physiologically active mono-amines in vivo and especially the level of adrenaline in the brain and hence exhibits different pharmacological effects (Japanese patent application first application "Kokai" Nos. 225044/83 and 112914/84; E.P. patent application publication No. 0112606; U.S. patent application Ser. No. 523,957 and U.S. patent application Ser. No. 768,345).
The L-threo-adrenalinecarboxylic acid is now studied for its pharmacological activities and expected to be useful as antidepressant and as anti-Parkinsonism drug.
On the other hand, L-threo-3-(3,4-dihydroxyphenyl) serine which is sometimes termed as L-threo-DOPS is known to have some activities on the circulatory system and psychotropic activities and also is expected to be useful as anti-Parkinsonism agent like to the known L-Dopa (Japanese patent application first publication "Kokai" Nos. 49252/75; 32540/76; 36233/79 and EP patent application publication No. 0024210).
In the recent years, we have continued our extensive research on the N-methyl-3-(3,4-dihydroxyphenyl)serine to find out that this compound exhibits various and useful physiological activities, and that N-methyl-L-threo-3-(3,4-dihydroxyphenyl)serine, namely the L-threo-adrenalinecarboxylic acid is able to penetrate into the brain of mammalian animals through the blood-brain barrier when administered intravenously or intraperitoneally and is able to increase the level of adrenaline in the brain through unknown biological mechanisms. As long as we are aware of, however, synthetic derivatives of the N-methyl-3-(3,4-dihydroxyphenyl)serine have not yet been produced and have not been disclosed in any literatures.
In an attempt to provide new compounds which can exhibit better pharmacological properties than the L-threo-adrenalinecarboxylic acid, we have studied on the synthetic production of new derivatives of N-methyl-3-(3,4-dihydroxyphenyl)serine. As a result, we have now found that such lower alkyl esters of the N-methyl-3-(3,4-dihydroxyphenyl)serine as represented by the general formula (I) shown below can be produced as the new compounds and are capable of exhibiting excellent pharmacological activities. In particular, we have found that N-methyl-L-threo-3-(3,4-dihydroxyphenyl)serine lower alkyl esters are able to exhibit higher activities of antagonising the psychopharmacological effects of reserpine in mammalian animals and of reducing the hypothermia and ptosis as induced by the administration of reserpine, and that the new compounds, N-methyl-3-(3,4-dihydroxyphenyl)serine lower alkyl esters (the carboxylates) and particularly N-methyl-L-threo-3-(3,4-dihydroxyphenyl)serine lower alkyl esters (the carboxylates) are active as a central nervous system stimulant and are expectable to be effective in therapeutic treatment of some disorders of the central nervous system of man, such as mental depressions, Parkinsonism and senile dementia. According to M. Bourin et al (the "Arzneim-Forsh." Vol. 33, (II), No. 8, 1173-1176 (1983)), the psychopharmacological study of the effects of various known 21 antidepressive or anti-Parkinsonism agents on the reserpine-induced hypothermia, ptosis and akinesia (reduction of motor activity) has revealed that such drugs stimulating the .beta.-adrenergic receptors of the central nervous system directly or indirectly are active to antagonise the reserpine-induced hypothermia, that such drugs stimulating the .alpha.-adrenergic or serotonergic receptors are active to antagonise the reserpine-induced ptosis (eyelid closing), and that such drugs stimulating the dopaminergic receptors are active to antagonise the reserpine-induced akinesia. Accordingly, we have now considered it evident from our tests that at least, the new compounds, N-methyl-L-threo-3-(3,4-dihydroxyphenyl)serine lower alkyl esters according to this invention are active to stimulate both the .alpha.- and .beta.-adrenergic functions of the central nervous system of mammalian animals. This is in contrast to that neither of the N-methyl-L-threo-3-(3,4-dihydroxyphenyl)serine (namely, the free L-threo-adrenalinecarboxylic acid) and L-threo-DOPS do actually antagonise the effect of reserpine to induce the ptosis and hence are evidently not active to stimulate the .alpha.-adrenergic functions, as demonstrated in our tests shown hereinafter.